Immediately disintegrable medicinal composition

ABSTRACT

The present invention relates to a pharmaceutical composition useful for rapid disintegration, which comprises a sparingly soluble medicament held on a gel-forming water-soluble polymer as a solid dispersion, wherein it contains a salt substance that comprises an alkali and a weak or strong acid and has an endothermic standard enthalpy of solution or heat of solution. Since rapid disintegration of the pharmaceutical composition of the present invention and rapid dissolution of the medicament contained in the preparation can be made in the digestive tracts pH-independently, good bioavailability can be attained.

TECHNICAL FIELD

[0001] This invention relates to a pharmaceutical composition whichcomprises a sparingly soluble medicament held on a water soluble polymeras a solid dispersion and exhibits rapid disintegration.

BACKGROUND ART

[0002] In order to effect remission and healing of the indication ofinterest by effectively expressing pharmacological effect of an activeingredient contained in a pharmaceutical preparation, it is needless tosay that appropriate dosage form and formulation of the pharmaceuticalpreparation must be selected depending not only on pharmacologicalproperties of the active ingredient but also on its physicochemicalproperties and the kind and disease state of the indication of interest.

[0003] However, it often occurs that a developed medical compoundselected based on its excellent pharmacological effects is sparinglysoluble in water despite of the expectation of fast-acting property inits indications.

[0004] Since sparingly soluble medicaments are also low in solubility inthe digestive tracts, it is general that not only their absorption fromthe digestive tracts is poor but also their fast-acting property cannotbe expected. In addition, in the case of a medicament which becomessparingly soluble depending on pH, its dissolution property is affectedby pH in the digestive tracts and meals of a patient, so that not onlyits bioavailability after administration is varied but also itsfast-acting property cannot be expected in some cases.

[0005] In consequence, it is still an important techinical problem todesign pharmaceutical preparations to solubilize sparingly solublemedicaments by certain means and to give rapidly disintegrable property,in expectation of attaining fast-acting property of the sparinglysoluble medicaments.

[0006] Known processes for improving solubility and absorption of asparingly soluble medicament include a process of finely dividing themedicament, a process for forming a solid dispersion, and the like.Among them, the process for forming a solid dispersion is considered tobe generally usable in practice for the improvement of solubility andabsorption of a sparingly soluble medicament (cf. an examined Japanesepatent publication 59-48810 corresponding to U.S. Pat. No. 4,673,564).

[0007] The process for forming a solid dispersion using a polymer baseto carry a sparingly soluble medicament is suited for a composition forsustained release preparation. It is however accompanied with thedisadvantage that the polymer base formed into a solid dispersion doesnot contribute to the disintegration at all so that a disintegratingrate of the preparation in the body liquid is slow, which delays thedissolution of the medicament and therefore fast-acting property cannotbe expected.

[0008] Also under investigation is a process for improving theabsorption of a sparingly soluble medicament hold in a solid dispersionand the disintegration of the preparation. Examples thereof includecompression molding obtained by granulating a mixture of a sparinglysoluble medicament and a specific polymer such as polyvinyl pyrrolidoneby fluidized bed granulation method, and a compression molding obtainedby granulating a mixture obtained by compounding a sparingly solublemedicament, one or more components selected from the group consisting ofPVP, urea, citric acid, mannitol, succinic acid, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose and amino acid, andone or more components selected from the group consisting of asurfactant, polyethylene glycol, propylene glycol, glycerol, glycerolfatty acid ester and plant oil by fluidized bed granulation method (cf.an unexamined published Japanese patent application 56-110612). However,there is room for improvement in the above method, particularly, indisintegrable effects. It is desired to establish a formulationtechnique generally used in practice, for example, by only mixing thecomponents and then compression molding the resultant mixture, withoutemploying the fluidized bed granulation method.

DISCLOSURE OF THE INVENTION

[0009] Under such a technical level, the present inventors examined thedisintegrable property of the preparation, which was obtained by addingto a composition having a newly developed sparingly soluble medicamentheld on a polymer base as a solid dispersion, with croscarmellose sodiumwhich was ordinarily used as a general-purpose strong disintegrant,carboxymethylcellulose calcium, starch, low-substituted hydroxypropylcellulose or the like. As a result, it was found that such adisintegrant could not impart a sufficient disintegrating property tothe preparation.

[0010] Paying attention to an effervescent preparation composed ofsodium bicarbonate and an organic acid such as citric acid or tartaricacid, the present inventors continued investigation. In general, themixed composition of an alkali and an acid is easily influenced byhumidity and therefore it is presumed to involve a problem in thestability. However, it was found unexpectedly that the addition ofsodium bicarbonate alone without adding any organic acid makes itpossible to impart a rapidly disintegrable property to the preparationand that addition of a specific salt as an alkali which is used for aneffervescent preparation also makes it possible to impart a rapidlydisintegrable property to the preparation. As a result of furtherinvestigation, it was found that a disintegrant used for a preparationhaving a sparingly soluble medicament held on a polymer base as a soliddispersion can impart the preparation with a desired disintegrableproperty if it is a salt which comprises an alkali and a weak or strongacid and has an endothermic standard enthalpy of solution or heat ofsolution, not being limited to sodium bicarbonate. Based on thisfinding, the present invention was accomplished. The disintegratingmechanism upon the addition of the such a substance has not been madeclear yet. However, since the heat of solution when such a substance isdissolved in water is endothermic, the present inventors consider thatthermodynamic effects suppress the gelation of a water-soluble polymerand, moreover, the suppression of gelation by salting-out effects of thesubstance having an endothermic standard enthalpy of solutionaccelerates the disintegration.

[0011] Accordingly, the present invention relates to a rapidlydisintegrable pharmaceutical composition which comprises a sparinglysoluble medicament held on a gel-forming water-soluble polymer as asolid dispersion, wherein it contains a salt substance that comprises analkali and a weak or strong acid and has an endothermic standardenthalpy of solution or heat of solution. The present invention alsorelates to a rapidly disintegrable pharmaceutical composition whichcomprises a surfactant and a sparingly soluble medicament held on agel-forming water-soluble polymer as a solid dispersion, wherein itcontains a salt substance that comprises an alkali and a weak or strongacid and has an endothermic standard enthalpy of solution or heat ofsolution. It also relates to a pharmaceutical preparation whichcomprises 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide or a salt thereofand a pharmaceutical carrier that exhibits the dissolution of 75% ofsaid medicament within 15 minutes when a test is performed using 500 mlof the first fluid (pH 1.2) at 100 r.p.m. in accordance with the secondmethod (paddle method) for dissolution specified in JapanesePharmacopoeia, 13th Edition.

[0012] It is known to add sodium bicarbonate to a sparingly solublemedicament to improve the dissolution property of the medicament or toadd antacid such as sodium bicarbonate to an oxicam-baseanti-inflammatory medicament to improve the dissolution and absorptionof the medicament (an unexamined published Japanese patent applicationNo. 2-704 corresponding to U.S. Pat. No. 5,091,191, and an unexaminedpublished Japanese patent application No. 3-240729). Such a medicamentis not a composition obtained by allowing a large amount of a polymerbase to hold the medicament thereon as a solid dispersion, but obtainedby using a polymer base upon mixing the medicament with sodiumbicarbonate or granulating the resulting mixture.

[0013] Hereinafter, the pharmaceutical composition of the presentinvention is described in more specifically.

[0014] With respect to the salt substance which comprises an alkali anda weak or strong acid and has an endothermic standard enthalpy ofsolution or heat of solution, the term “standard enthalpy of heat” asused herein means a dissolving enthalpy (kJ/mol) at the time when anaqueous solution of standard conditions is produced from 1 mole of asubstance under standard conditions.

[0015] In addition to the embodiment of the present invention whichcomprises a salt substance which comprises an alkali and a weak orstrong acid, has disintegration improving effects, and has anendothermic standard enthalpy of solution or heat of solution, thepresent invention embrace an embodiment which further comprises anordinarily used disintegrant. The present invention also embraces anembodiment within an extent not impairing the object of the presentinvention, more specifically, the embodiment which further comprises anorganic acid such as citric acid within an extent not affecting the pHof digestive tracts.

[0016] The sparingly soluble medicament to be used in the presentinvention is not particularly limited. Its examples include those whichshow a solubility of 100 ml or more, preferably 1,000 ml or more, morepreferably 10,000 ml of more, as the volume of solvent required fordissolving 1 g of each medicament, which is calculated by powdering themedicament, putting the powder into a solvent such as water, the firstfluid or the second fluid and then measuring the solubility within 30minutes when the suspension is vigorously shaken for 30 seconds at 20±5°C. at intervals of 5 minutes. The first fluid and second fluid as usedherein are specified in the disintegration test of JapanesePharmacopoeia, 13th Edition. For example, the first fluid is an aqueoussolution having a pH value of about 1.2 prepared by filling up 2 g ofsodium chloride and 7.0 ml of hydrochloric acid to 1,000 ml with water,and the second fluid is an aqueous solution having a pH value of about6.8 prepared by filling up 250 ml of 0.2 M potassium dihydrogenphosphateaqueous solution and 118 ml of 0.2 N sodium hydroxide aqueous solutionto 1,000 ml with water. Examples of the sparingly soluble medicamentinclude central nervous system drugs, circulatory organ system drugs,respiratory organ system drugs, digestive organ system drugs,antibiotics, chemotherapeutic agents, metabolic system drugs and vitamindrugs, all of which being sparingly soluble. A medicament which requiresfast-acting property can be cited as a preferred example of thesparingly soluble medicament to be used in the present invention. Itsillustrative examples include 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1] benzoazepine-6-carbonyl)-2-phenylbenzanilide or a saltthereof which is a known compound disclosed in International Publication95/03305 (to be referred simply to as “Compound A” hereinafter in somecases, and its hydrochloride as “Compound A1”),(Z)-4′-[[4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonyl]methylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl]carbonyl]-2-phenylbenzanilideor a salt thereof which is a known compound disclosed in InternationalPublication 95/06035 and1-[2,3-dihydro-1-(O-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzoazepin-3-yl]-3-(m-tolyl)ureawhich is a known compound disclosed in International Publication92/11246 (to be referred to as “Compound B” hereinafter in some cases),of which Compound A is preferred, and Compound A1 is more preferred.

[0017] The Compound A is created by the inventors in the company of thepresent applicant, which has excellent antagonism for argininevasopressin V1 and/or V2 receptor. Based on the profile of thisfunction, it shows water diuretic action, urea excretion enhancingaction, factor VIII secretion inhibition action, vasodilation action,cardiac function acceleration action, mesangial cell contraction action,mesangial cell growth inhibition action, hepatic gluconeogenesis action,platelet agglutination inhibition action, aldosterone secretioninhibition action, endothelin production inhibition action, centralbuffer controlling action, renin secretion controlling action, memorycontrolling action, body temperature controlling action andprostaglandin production controlling action, is useful as characteristicwater diuretic agent, urea excretion enhancing agent, vasodilator drug,hypotensive drug, anti-cardiac failure agent, anti-renal failure agentand blood coagulation inhibitor and is effective in preventing and/ortreating diseases such as cardiac failure, hyponatremia, syndrome ofinappropriate secretion of antidiuretic hormone (SIADH), hypertension,renal insufficiency, (nephrosis, glomerular nephritis, diabeticnaphropathy, chronic or acute renal failure), edema, brain edema,ascites, hepatic cirrhosis, hypokalemia, water metabolism disorder,diabetes, various ischemic diseases, cerebrovascular accidents,circulatory failure, gastric ulcer, nausea, emesis, syncope and renalfunction disorder and also in alleviating secondary diseases of cerebralinfarction and cerebral bleeding.

[0018] Since said compound is sparingly soluble in water, it becomes animportant technical problem to solubilize Compound A upon designing ofits preparation, thereby attaining good bioavailability. In addition,since this compound is expected to increase urine volume due to itspharmacological effects, rapid expression of drug efficacy afteradministration after supper is desired in order to prevent theexpression of drug efficacy while sleeping. It is therefore an importanttechnical problem to impart both rapid disintegration and rapiddissolution properties to a pharmaceutical preparation containingCompound A upon designing of the preparation.

[0019] For exhibiting a fast-acting property of Compound A used in thepresent invention, it is necessary for the pharmaceutical preparation todisintegrate rapidly, thereby rapidly dissolving the medicamentcontained in the preparation. An example for its evaluation standards isas follows. When a pharmaceutical preparation (e.g., in the form of atablet) containing Compound A is subjected to a test by using 500 ml ofthe first fluid (pH: 1.2) at 100 r.p.m. in accordance with the secondmethod (paddle method) of the dissolution test method specified inJapanese Pharmacopoeia, 13th Edition, a time required for thedissolution of 75% of Compound A is within 15 minutes. Preferably, atime required for the dissolution of 75% of Compound A is within 10minutes. The carrier for the preparation is not particularly limited aslong as it shows such dissolution behavior. The amount of Compound A isnot particularly limited as long as it is a pharmacological amountordinarily used for the treatment.

[0020] The gel-forming water-soluble polymer usable in the presentinvention is not particularly limited as long as Compound A cangenerally be held on it as a solid dispersion. Preferred are cellulosederivatives. Specific examples of the cellulose derivative includehydroxypropylmethylcellulose (for example, “TC-5E”, “Metolose 90”,“Metolose 65SH”, each trade name; produced by Shin-Etsu Chemical Co.,Ltd.), hydroxypropylcellulose (for example, “Nisso HPC”, trade name;produced by Nippon Soda Co., Ltd.), methyl cellulose (for example,“Metolose SM”, trade name; produced by Shin-Etsu Chemical Co., Ltd.),and hydroxyethylcellulose (“NATROSOL”, trade name; produced by HerculesJapan, Ltd.). More preferred is hydroxypropylmethylcellulose. Thesegel-forming water-soluble polymers can be used either singly or incombination.

[0021] In order to increase the solubility of the solid dispersion ofthe present invention, a surfactant may be added. The surfactant is notparticularly limited as long as it is pharmaceutically acceptable.Examples thereof include anionic surfactants such as sodium alkylsulfateand nonionic surfactants such as polyoxyethylene sorbitan fatty acidesters (for example, Polysorbate 80; “Rheodol TW-0120”, trade name;produced by Kao Corp.), polyoxyethylene fatty acid esters andpolyoxyethylene castor oil derivatives (for example, polyoxyethylenehydrogenated castor oil (60); “HCO-60”, trade name; produced by NikkoChemicals Co., Ltd.). These surfactants may be used either singly or incombination.

[0022] When a solid dispersion of a sparingly soluble medicament and agel-forming water-soluble polymer or a solid dispersion of a sparinglysoluble medicament, a gel-forming water-soluble polymer and asurfactant, each to be used in the present invention, is prepared, thegel-forming water-soluble polymer is added in an amount of 0.5 to 20parts by weight, preferably 1 to 10 parts by weight, more preferably 1to 5 parts by weight, based on 1 part by weight of the sparingly solublemedicament. The surfactant is added in an amount of 0.1 to 3 parts byweight, preferably 0.2 to 1.5 parts by weight, more preferably 0.25 to1.25 parts by weight based on 1 part by weight of the sparingly solublemedicament.

[0023] Examples of the salt substance used in the present invention,which comprises an alkali and a weak or strong acid and has anendothermic standard enthalpy of solution or heat of solution (which mayhereinafter be abbreviated as “disintegrable improver”, simply) includesodium bicarbonate (19.1 kJ/mol, 4.3 kcal/mol), potassium bicarbonate(5.3 kcal/mol), potassium sulfate (23.7 kJ/mol, 6.38 kcal/mol),potassium chloride (17.2 kJ/mol, 4.19 kcal/mol), sodium chloride (3.9kJ/mol, 1.18 kcal/mol) and potassium dihydrogenphosphate (19.6 kJ/mol,4.85 kcal/mol) . Among them, preferred are sodium bicarbonate, potassiumbicarbonate, potassium sulfate and potassium dihydrogenphosphate. Sodiumbicarbonate and/or potassium bicarbonate are more preferred, and sodiumbicarbonate is still more preferred. These disintegrable improvers maybe used either singly or in combination.

[0024] The amount of the disintegrable improver used in the presentinvention is not particularly limited as long as it is apharmaceutically acceptable amount. It is preferably added in an amountof at least 0.1 part by weight, more preferably 0.1 to 6 parts byweight, still more preferably 0.3 to 1 part by weight based on 1 part byweight of the gel-forming water-soluble polymer. Amounts smaller than0.1 part by weight show small effects, and it is desired to suppress theamount of an excipient upon formulation.

[0025] The sparingly soluble medicament, gel-forming water-solublepolymer, surfactant and disintegrable improver are added in amounts(wt./wt. %) of 1 to 30%, 3 to 60%, 0 to 20% and 3 to 50%, respectively,preferably 3 to 15%, 10 to 50%, 0 to 10% and 5 to 30%, respectively,each based on the total amount of the preparation.

[0026] A preferred pharmaceutical composition or pharmaceuticalpreparation according to the present invention is that comprisinghydroxypropylmethylcellulose as the gel-forming water-soluble polymer,sodium bicarbonate as a salt substance which comprises an alkali and aweak or strong acid and has an endothermic standard enthalpy of solutionor heat of solution, and optional a polyoxyethylene sorbitan fatty acidester as a surfactant.

[0027] Hereinafter, the pharmaceutical composition or the manufacturingprocess for the preparation of the preparation comprising the sameaccording to the present invention will be described in detail.

[0028] A composition which comprises a sparingly soluble medicament heldon a gel-forming water-soluble polymer as a solid dispersion and a soliddispersion which comprises a sparingly soluble medicament held on agel-forming water-soluble polymer containing a surfactant can beprepared in a known manner. For example, a sparingly soluble medicament,a surfactant, etc. can be prepared by suspending or dissolving CompoundA and a gel-forming water-soluble polymer and an optional surfactant inwater or an organic solvent (e.g., a lower alcohol such as methanol orethanol, or a halogen-based organic solvent such as dichloromethane) andthen spray drying the solution or suspension. Alternatively, the soliddispersion may be prepared by the step of spraying the solution orsuspension to an excipient, and then granulating.

[0029] The granulation can be carried out in a known manner, forexample, by a fluidized bed granulator (manufactured by OkawaraSeisakujo), a vertical mixer (manufactured by San-Ei Seisakujo) or anagitating granulator (manufactured by Fukae Kogyo). In the case of afluidized bed granulator, granulation is carried out by generallyoperable conditions, for example, at a spray pressure of 0.3 to 3 kg/cm²and product temperature of 20 to 45° C. until the granule size reachesthe desired level.

[0030] The pharmaceutical preparation of the present invention can beused in the form of tablets, granules or capsules. Among them,compression-molded tablets and capsules having a solid dispersion filledtherein exhibit more desirable effects of the present invention.Preparations in such forms can be prepared in a known manner.

[0031] For example, tablets can be prepared on a single punch tablettingmachine (manufactured by Kikusui Seisakujo) or rotary tabletting machine(manufactured by Hata Seisakujo). The molding pressure upon tablettingmay be set as desired based on the hardness, disintegrable property,etc. of the molded product and is not particularly limited. Examples ofthe molding pressure include 0.3 ton/punch to 1 ton/punch.

[0032] Such a pharmaceutical preparation can be prepared in a knownmanner by using, for example, as an additive, an excipient such aslactose, corn starch, light anhydrous silicic acid, microcrystallinecellulose or crystalline cellulose (“Avicel PH102”, trade name; productof Asahi Kasei); a binder such as a starch, methylcellulose,carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinyl pyrrolidone, gum arabic powder,gelatin or pullulan; a disintegrant such as croscarmellose sodium(“Ac-Di-Sol”, trade name; produced by Asahi Kasei),carboxymethylcellulose calcium, starch or low-substitutedhydroxypropylcellulose; a surfactant such as “Polysorbate 80” (producedby Kao Astra Co., Ltd.), polyoxyethylene hydrogenated castor oil(“HCO-60”, trade name; product by Nikko Chemicals) or “PLURONIC F68”(polyoxyethylene BP. polyoxypropylene copolymerized substance; producedby Asahi Denka Kogyo K.K.); antioxidant such as sodium sulfite or sodiumascorbate; lubricant such as magnesium stearate, calcium stearate, talc,sucrose fatty acid ester, polyethylene glycol or stearic acid; souragent such as citric acid, tartaric acid or malic acid; artificialsweetener such as sodium saccharin, dipotassium glycyrrhizinate,aspartame, stevia or somatin; flavor such as lemon, lemon lime, orangeor menthol; colorant such as Food Yellow 5, Food Red 2 or Food Blue 2;and stabilizer.

[0033] In order to suppress the taste, the solid dispersion in thetablet or granule preparation, or the tablet or granule preaprationitself may be coated in a known manner. Examples of the coating agentinclude hydroxypropylcellulose, ethylcellulose, hydroxymethylcelluloseand hydroxypropylcellulose. They may be used either singly or incombination and coating of a single layer or two or more layers ispossible. The coating is carried out in a known manner, for example, bythe pan coating method, fluidized bed coating method or tumbling coatingmethod through spraying a dispersion or solution of a coating base inwater or an organic solvent.

BEST MODE FOR CARRYING OUT THE INVENTION

[0034] Hereinafter, the present invention will be specifically describedwith reference to Examples. It should however be understood that thescope of the present invention is not limited to or by Examples.Incidentally, preparations obtained in Examples and Comparative Exampleswere evaluated according to the disintegration property test wasevaluated by the dissolution test or disintegration test.

[0035] [Dissolution Test]

[0036] With respect to the tablets prepared in Examples 1 to 5 andComparative Examples 1 to 3, a test was performed at 100 r.p.m. in 500ml of a first fluid (pH: 1.2) as specified in the disintegration testmethod of Japanese Pharmacopoeia by employing the second method (paddlemethod) of the dissolution test method of Japanese Pharmacopoeia, 13thEdition and a time required for dissolution of 75% of the medicament wasmeasured.

[0037] [Disintegration Test]

[0038] With respect to the tablets obtained in Examples 6 to 8, a testwas performed in accordance with the disintegration test method ofJapanese Pharmacopoeia, 13th Edition using water as the test solution.

[0039] Preparation of a Solid Dispersion of Compound A1

[0040] In 45.5 parts by weight of a 9:1 by weight mixed solution ofmethanol and water, 1 part by weight of Compound A1, 3 parts by weightof “HPMC 2910” and 0.5 parts by weight of “Polysorbate 80” weredissolved, and a solid dispersion was prepared by spray drying.

EXAMPLE 1

[0041] 45 mg of the solid dispersion obtained above (preparation of asolid dispersion of Compound A1), 75 mg of lactose and 30 mg of sodiumbicarbonate were uniformly mixed. The resulting mixture was formed intotablets each having a weight of 150 mg (Compound A1: 10 mg) and adiameter of 7.5 mm by an oil press at a tabletting pressure of 500kg/punch. The result of the dissolution test was 4 minutes.

EXAMPLE 2

[0042] 45 mg of the solid dispersion obtained above (preparation of asolid dispersion of Compound A1), 90 mg of lactose and 15 mg of sodiumbicarbonate were uniformly mixed. The resulting mixture was formed intotablets each having a weight of 150 mg (Compound Al: 10 mg) and adiameter of 7.5 mm by an oil press at a tabletting pressure of 500kg/punch. The result of the dissolution test was 5 minutes.

EXAMPLE 3

[0043] 45 mg of the solid dispersion obtained above (preparation of asolid dispersion of Compound A1), 75 mg of lactose and 30 mg ofpotassium bicarbonate were uniformly mixed. The resulting mixture wasformed into tablets each having a weight of 150 mg (Compound A1: 10 mg)and a diameter of 7.5 mm by an oil press at a tabletting pressure of 500kg/punch. The result of the dissolution test was 5 minutes.

EXAMPLE 4

[0044] In 4,550 g of a 9:1 by weight mixed solution of methanol andwater, 100 g of Compound A1, 300 g of “HPMC 2910” and 50 g of“Polysorbate 80” were dissolved. Then, by using a fluidized bedgranulator (“Uniglatt”, manufactured by Okawara Seisakujo), 442 g oflactose and 150 g of sodium bicarbonate were fluidized and the solutionprepared above was sprayed to the fluidized mixture, whereby granulatedpowder was obtained. Then, 834 g of the resulting granulated powder, 240g of crystalline cellulose (“Avicel PH102”, trade name; produced byAsahi Kasei), 120 g of croscarmellose sodium (“Ac-Di-Sol”, trade name;produced by Asahi Kasei) and 6 g of magnesium stearate were uniformlymixed. The resulting mixture was formed into tablets each having aweight of 150 mg (Compound A1: 10 mg) and a diameter of 7.5 mm by arotary tabletting machine (manufactured by Hata Seisakujo) at atabletting pressure of 700 kg/punch. The result of the dissolution testwas 9 minutes.

EXAMPLE 5

[0045] In 4,550 g of a 9:1 by weight mixed solution of methanol andwater, 100 g of Compound A1, 300 g of “HPMC 2910” and 50 g ofpolyethylene hydrogenated castor oil (60) (“Nikkol 60”, trade name;produced by Nikko Chemicals) were dissolved. Then, by using a fluidizedbed granulator (“Uniglatt”, manufactured by Okawara Seisakujo), 435 g oflactose and 150 g of sodium bicarbonate were fluidized and the solutionobtained above was sprayed to the fluidized mixture, whereby granulatedpowder was prepared. Then, 828 g of the resulting granulated powder and1572 g of lactose were mixed uniformly, and the resulting mixture wasfilled into capsules (No. 1 capsule) each in an amount of 0.3 g(Compound A1: 10 mg) per capsule, whereby preparing capsules. The resultof the dissolution test was about 4 minutes.

COMPARATIVE EXAMPLE 1

[0046] 45 mg of the solid dispersion obtained above (in the preparationof a solid dispersion of Compound A1), 75 mg of lactose and 30 mg ofcroscarmellose sodium (“Ac-Di-sol”, trade name; produced by Asahi Kasei)were uniformly mixed. The resulting mixture was formed into tablets eachhaving a weight of 150 mg (Compound A1: 10 mg) and a diameter of 7.5 mmby an oil press at a tabletting pressure of 500 kg/punch. The result ofthe dissolution test was 48 minutes.

COMPARATIVE EXAMPLE 2

[0047] 45 mg of the solid dispersion obtained above (in the preparationof a solid dispersion of Compound A1), 75 mg of lactose and 30 mg ofcarboxymethyl starch sodium (“Primojel”, trade name; produced byMatsutani Chemical) were uniformly mixed. The resulting mixture wasformed into tablets each having a weight of 150 mg (Compound A1: 10 mg)and a diameter of 7.5 mm by an oil press at a tabletting pressure of 500kg/punch. The result of the dissolution test was 27 minutes.

COMPARATIVE EXAMPLE 3

[0048] 45 mg of the solid dispersion obtained above (in the preparationof a solid dispersion of Compound A1), 75 mg of lactose and 30 mg ofsodium carbonate were uniformly mixed. The resulting mixture was formedinto tablets each having a weight of 150 mg (Compound A1: 10 mg) and adiameter of 7.5 mm by an oil press at a tabletting pressure of 500kg/punch. The result of the dissolution test was 55 minutes.

[0049] Results of Dissolution Test

[0050] Preparations of the present invention which had been obtained inExamples 1 to 5 were subjected to the dissolution test, each resultingin the dissolution time within 9 minutes. On the other hand,preparations obtained in Comparative Examples 1 to 3 were subjected to adissolution test, each resulting in the dissolution time of 27 minutesor longer (cf. Table 1).

[0051] The disintegrant which was ordinarily used and the salt substancewhich comprises an alkali and a weak or strong acid and having not anendothermic standard enthalpy of solution, that is, having an exothermicstandard enthalpy of solution like sodium carbonate (−26.7 kJ/mol) whichwas used as an effervescence tablet did not attain rapid disintegration.On the other hand, it was confirmed that the preparations according tothe present invention each exhibited a rapidly disintegrable property.TABLE 1 Comparative Examples Examples 1 2 3 4 5 1 2 3 Disso- 4 5 5 9 448 27 55 lution test (min)

[0052] Preparation of a Solid Dispersion of Compound B

[0053] In methanol, 1 g of Compound B, 3.5 g of “HPMC 2910” and 0.5 g ofpolyoxyethylene hydrogenated castor oil (“HCO-60”, trade name; producedby Nikko Chemicals) were dissolved, and a solid dispersion was preparedby spray drying.

EXAMPLE 6

[0054] Then, 100 mg of the the solid dispersion obtained above(preparation of a solid dispersion of Compound B) and 50 mg of sodiumbicarbonate were mixed uniformly. The resulting mixture was formed intotablets each having a weight of 150 mg and a diameter of 7.5 mm by anoil press at 15 a tabletting pressure of 500 kg/punch. The result of thedisintegration test was 10 minutes.

EXAMPLE 7

[0055] A 200 mg portion of the solid dispersion obtained above (in thepreparation of a solid dispersion of Compound B) and 75 mg of sodiumbicarbonate were uniformly mixed, and the resulting mixture was formedinto tablets each having a weight of 275 mg and a diameter of 7.5 mm byan oil press under a tabletting pressure of 500 kg/punch. The result ofthe dissolution test was 15 minutes.

EXAMPLE 8

[0056] A 200 mg portion of the solid dispersion obtained above (in thepreparation of a solid dispersion of Compound B) and 100 mg of sodiumbicarbonate were uniformly mixed, and the resulting mixture was formedinto tablets each having a weight of 300 mg and a diameter of 7.5 mm byan oil press under a tabletting pressure of 500 kg/punch. The result ofthe dissolution test was 10 minutes.

[0057] Results of Dissolution Test

[0058] Results of the dissolution test carried out on the tabletsobtained in Examples 6 to 8 were all within 15 minutes.

[0059] In consequence, the pharmaceutical composition of the presentinvention exhibits rapid disintegration of sparingly soluble medicamentshaving completely different structures regardless of the presence orabsence of their salts and is a medicament preparation technique havinghigh general-purpose performance.

Industrial Applicability

[0060] The pharmaceutical composition according to the present inventionexhibits rapid disintegration. Owing to rapid dissolution of a sparinglysoluble medicament from the composition, good bioavailability can beattained. In addition, the preparation comprising the abovepharmaceutical composition therefore exhibits rapid disintegrationindependently of the pH in the digestive tract and the medicamentcontained in the preparation exhibits rapid dissolution.

1. A rapidly disintegrable pharmaceutical composition which comprises asparingly soluble medicament held on a gel-forming water-soluble polymeras a solid dispersion, wherein it contains a salt substance thatcomprises an alkali and a weak or strong acid and has an endothermicstandard enthalpy of solution (KJ/mol) or heat of solution (Kcal/mol).2. A rapidly disintegrable pharmaceutical composition according to claim1, which further comprises a surfactant, wherein it contains a saltsubstance that comprises an alkali and a weak or strong acid and has anendothermic standard enthalpy of solution or heat of solution.
 3. Arapidly disintegrable pharmaceutical composition according to claim 1 or2, wherein the salt substance that comprises an alkali and a weak orstrong acid and has an endothermic standard enthalpy of solution or heatof solution is at least one substance selected from the group consistingof sodium bicarbonate, potassium bicarbonate, potassium sulfate,potassium chloride, sodium chloride and potassium dihydrogenphosphate.4. A rapidly disintegrable pharmaceutical composition according to claim3, wherein the salt substance that comprises an alkali and a weak orstrong acid and has an endothermic standard enthalpy of solution or heatof solution is sodium bicarbonate and/or potassium bicarbonate.
 5. Arapidly disintegrable pharmaceutical composition according to any one ofclaims 1 to 4, wherein the salt substance that comprises an alkali and aweak or strong acid and has an endothermic standard enthalpy of solutionor heat of solution is contained in an amount of 0.1 part by weight ormore based on 1 part by weight of the gel-forming water-soluble polymer.6. A rapidly disintegrable pharmaceutical composition according to claim5, wherein the salt substance that comprises an alkali and a weak orstrong acid and has an endothermic standard enthalpy of solution or heatof solution is contained in an amount of from 0.1 to 6 parts by weightbased on 1 part by weight of the gel-forming water-soluble polymer.
 7. Arapidly disintegrable pharmaceutical composition according to any one ofclaims 1 to 6, which is in the form of tablets, granules or capsules. 8.A rapidly disintegrable pharmaceutical composition according to any oneof claims 1 to 7, wherein the sparingly soluble medicament is4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepin-6-yl)carbonyl]-2-phenylbenzanilide or a salt thereof.
 9. Apharmaceutical preparation which comprises4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepin-6-yl)carbonyl]-2-phenylbenzanilide or a salt thereof and apharmaceutical carrier that exhibits the dissolution of 75% of saidmedicament within 15 minutes when a test is performed using 500 ml ofthe first fluid (pH 1.2) at 100 r.p.m. in accordance with the secondmethod (paddle method) for dissolution specified in JapanesePharmacopoeia, 13th Edition.
 10. A pharmaceutical preparation accordingto claim 9, wherein the pharmaceutical carrier as claimed in claim 9comprises a gel-forming water-soluble polymer, a surfactant and a saltsubstance that comprises an alkali and a weak or strong acid and has anendothermic standard enthalpy of solution or heat of solution.